Role of corticosteroids in acute asthma

Traditional treatmentOccasional RelieversIdeal treatment CorticosteroidsRegular ControllersNeed for a corticosteroid treatment in asthma

Need for a corticosteroid treatment in acute asthmaBoth oral & IV steroids appear to have equivalent effects.

Extremely effective in reducing airway inflammation.

Corticosteroids given in moderate to high doses:

Speed resolution of exacerbations Reduce admissionsImprove pulmonary function.Systemic corticosteroids are considered in the management of all but mildest exacerbations of asthma.Corticosteroids are the most effective drugs to suppress airway inflammationGlobal Initiative for Asthma (GINA) - 2009

Need for a corticosteroid treatmentEarly intervention alters the chronic progressive nature of the disease.May play a key role in the reduction of permanent lung damage.Reduces the airway inflammation by:Potent vasoconstriction activity in airwayDecrease activation & recruitment of inflammatory cellsDecrease secretion from mucus glandsPrevent leakage from endothelial cells

Clinics in chest medicine, vol 21, no. 2. June 2002

Ann Intern Med. 2003;139:359-370.Anti-inflammatory effects

Systemic CorticosteroidsRequire between 6 to 24 hours to improve pulmonary function.

Dose response relationship is difficult to prove.

Even single short courses of SCS may cause HPA axis suppression which rapidly returns to normal. But; markers of bone metabolism can remain abnormal for several weeks.

There is striking inconsistency in the use of SCS to treat acute asthma.

Chest 2006; 130:13011311 Clin Cornerstone 4 (6) :1-17, 2002Expert Rev Clin Immunol 4 (6):723-729, 2008Curr Opin Allergy Clin Immunol 3 (3): 169-175, 2003

Do we have other options?

Inhaled corticosteroidsEffective as a part of therapy for asthma exacerbations

Targeted delivery

Evidence for greater bronchodilation when beta agonists used along with ICS.

Can be as effective as OCS in preventing relapses.

Less dosages required to produce therapeutic effect compared to OCS.

GINA 2009

Nebulised corticosteroidsCan effectively be used in:

Chronic severe asthma

Very effective in all patients with acute asthma

Rapid effects: 1-2 hrs to produce therapeutic effects

Topical effect: vasoconstriction in airway mucosa

A potential alternative to SCS in acute asthma not requiring hospitalization.

In steroid dependent asthmatics to reduce the maintenance dose of oral steroids thereby reducing the risk of adverse effects.Chest 2006; 130:13011311 Clin Cornerstone 4 (6) :1-17, 2002Expert Rev Clin Immunol 4 (6):723-729, 2008Curr Opin Allergy Clin Immunol 3 (3): 169-175, 2003

Nebulization therapy is useful when-Acute attacks of Asthma /COPD

Immediate relief is required

High doses of bronchodilators and steroids are to be given along with the oxygen supply.

Patient is critical / unconscious

Unable to co-ordinate with inhaled devices like MDI/ DPI

Patients do not respond to regular treatment

Why nebulization?Useful in acute symptoms of Asthma and COPD

Most convenient way to give optimal dose and targeted drug delivery

Oxygen can be supplied along with the high dose drugs

Can be used in infants , children and elderly

Home management of severe conditions when patient is unable to co-ordinate with inhalation devices

Intravenous drug delivery can lead to increased risk of side effects

Require minimal patient cooperation and coordination

Do not require propellants

Aerosol generated has a high fine-particle fraction resulting in highly efficient delivery

Guideline RecommendationThe combination of high dose inhaled corticosteroids and salbutamol in acute asthma results in

Greater bronchodilation than salbutamol alone

Greater benefit than the addition of systemic corticosteroids

Reduced hospitalizations, especially for patients with more severe attacksGINA 2009

Why rapid effects with inhaled corticosteroids?A different mechanism of action

How do steroids act?SteroidsBind to receptors in the cytoplasmSteroid receptor complex travels to the nucleusWhere it binds with DNAAlters the expression of genesAnti-inflammatory proteins synthesisAnti-inflammatory effectsAnti-inflammatory effects without effect on genesNitric oxideOther mechanisms???

Genomic action of steroids

European J Pharmacology 2008;585:483-91Proc Am Thorac Soc 2004;1:255-63New Engl J Med 2005;353:1711-23

Non-Genomic action of steroidsEnzymes ?Transporters ?eNO ?

Genomic vs. Non genomic

Flohale respules

Fluticasone propionate Topically active glucocorticosteroid Derived from the 17-carbothioate series of androstane analogues Halogenated with two fluorines substituted at positions 6 and 9 This helps to increase the potency

High lipophilicityIncreased deposition in the lung

Slower release from the lung/ lipid compartment

Longer pulmonary residence time

Prolonged exposure of drug to receptor

Increased anti inflammatory effectLipophilicity - Fluticasone >BDP>Budesonide

300 times more than budesonide 3 times more than BDP

High lipophilicity of fluticasone so ensures high anti-inflammatory activity Higher vasoconstrictor potency of fluticasone ensures higher topical activity at half the dose of budesonide.High anti-inflammatory activity

FluticasoneBudesonideLipophilicity3001

FluticasoneBudesonideVasoconstrictor Potency41

Safe corticosteroidLesser oral bioavailability of fluticasone ensures least systemic side effects, giving you the reason to trust Flohale respules

FluticasoneBudesonideOral bioavailability< 1%11%

Long ActingHigher affinity towards receptor of fluticasone increases uptake and retention in airway tissue. Thereby making Flohale respules a long acting corticosteroid

FluticasoneBudesonideRelative receptor affinity1800935

Nebulised FluticasoneClinical efficacy and safety

Multi-centre, randomized, double-blind, parallel group design

N = 321

Aged 4-16 years old

Presented with an acute exacerbation of asthma

Randomly allocated to either Nebulized FP (1 mg BID) or Oral prednisolone for 7 days

Respir Med. 2000 Dec;94(12):1206-14.

Lung functionPEF (L/min)Respir Med. 2000 Dec;94(12):1206-14.

Chart1

179170

264248

FP

PDN

Sheet1

FPPDNSeries 3

day 11791702

day 72642482

Category 33.51.83

Category 44.52.85

To resize chart data range, drag lower right corner of range.

FEV1 & FVC(liters)Respir Med. 2000 Dec;94(12):1206-14.

Chart1

1.341.35

1.651.72

1.651.73

1.922.16

FP

PDN

Sheet1

FPPDNSeries 3

FEV1 on day 11.341.352

FEV1 onday71.651.722

FVC on day11.651.733

FVC on day 71.922.165

To resize chart data range, drag lower right corner of range.

Morning & evening PEFRRespir Med. 2000 Dec;94(12):1206-14.

ResultsBoth treatments reduced symptom scores to a similar extent.

The two treatments were well tolerated, and there was no difference in the incidence of adverse events.

Nebulized FP is at least as effective as oral prednisolone in the treatment of an acute exacerbation of asthma.Respir Med. 2000 Dec;94(12):1206-14.

Multicenter, randomized, double blind, double dummy, parallel group studyN = 413Mean age= 43 yearsPrimary outcome = treatment failurePEF < 60%Symptom score 3Patient withdrawalFluticasone propionate (2 mg daily) A short reducing course of oral prednisolone (starting at 40 mg / day and reducing by 5 mg every other day)

Thorax 1996;51: 1087-1092

Proportion of treatment failureThorax 1996;51: 1087-1092

Morning PEFThorax 1996;51: 1087-1092

Conclusion There is no evidence of a significant difference in efficacy between a reducing dose course of oral prednisolone and high dose inhaled fluticasone propionate in mild exacerbations of asthma which do not require admission to hospital.

Thorax 1996;51: 1087-1092

N=106

Mean age = 33.5 + 8.8 years

Randomly assigned to receive Fluticasone (3 mg/hour) or 500 mg of intravenous hydrocortisone.

Am J Respir Crit Care Med. 2005 Jun 1;171(11):1231-6.

Fluticasone group showed 30.5 % greater improvements in PEF compared with the hydrocortisone group. Am J Respir Crit Care Med. 2005 Jun 1;171(11):1231-6.

Fluticasone group showed 46.4% greater improvements in FEV1compared with the hydrocortisone group. Am J Respir Crit Care Med. 2005 Jun 1;171(11):1231-6.

RESULTSFluticasone group showed higher rates of patients who obtained the discharge threshold.

Subjects treated with fluticasone showed a significant decrease in hospitalization rate (p = 0.05)

Am J Respir Crit Care Med. 2005 Jun 1;171(11):1231-6.The use of repeated doses of inhaled fluticasone was more effective than intravenous hydrocortisone associated with an early improvement

Locally delivered steroids by inhalers or nebulizers have been shown in small trials to be effective in acute asthma attack.

N = 73; Age = 17-75 years

IMAJ 2008;10:568571.

Objectives: To determine the efficacy of nebulized compared to systemic steroids in adult asthmatics admitted to the emergency department following an acute attack.

Methods: Adult asthmatics admitted to the ED were assigned in random consecutive case fashion to one of three protocol groups:IMAJ 2008;10:568571.

Mean PEFR (% of predicted)IMAJ 2008;10:568571.

Chart1

42.435.238.9

51.739.347.4

group 1 (FP)

group 2 (MPDN)

group 3 (Both)

Sheet1

group 1 (FP)group 2 (MPDN)group 3 (Both)

on admission [p=0.288]42.435.238.9

after 2 hours [p=0.021]51.739.347.4

p value3.51.83

Category 44.52.85

To resize chart data range, drag lower right corner of range.

IMAJ 2008;10:568571.

ConclusionThis study cohort showed the advantage of nebulized steroid fluticasone vs. systemic corticosteroids in adult asthmatics managed in the ED following an acute attack.

Results suggest that nebulized steroids should be used, either alone or in combination with systemic steroids, to treat adults suffering acute asthma attack.

IMAJ 2008;10:568571.

N= 40

Mean age= 45 + 13 years

Duration= 24 month

Compared biological markers along with clinical & functional parameters.

During attack, sputum was collected spontaneously or by induction.

Pulmonary Pharmacology & Therapeutics 19 (2006) 353360

Results FP is effective at least as well as P in reducing sputum eosinophilia and in improving airway obstruction due to asthma exacerbation.Pulmonary Pharmacology & Therapeutics 19 (2006) 353360

Chart2

0.380.1

0.030.073

0.520.07

0.110.02

sputum eosinophil count

blood eosinophil count

Biological Markers

Sheet1

sputum eosinophil countblood eosinophil count

visit 1FP38%10%

visit 2FP3%7.30%

visit 1PDN52%7%

visit 2PDN11%2%

Sheet1

sputum eosinophil count

blood eosinophil count

Biological Markers

Sheet2

Sheet3

Multicenter, randomized, single-blind, parallel group design.

N= 168

Age= 4-15 years

randomly allocated to receive either nebulized FP (250 mcg) or nebulized BUD (500 mcg) twice daily for 10 days.

J Asthma. 2005 Jun;42(5):331-6

RESULTSImprovement of morning PEF was significantly higher in patients treated with FP.

J Asthma. 2005 Jun;42(5):331-6There was no evidence of HPA axis suppression.

ConclusionJ Asthma. 2005 Jun;42(5):331-6

A short course of nebulized FP has the same effects as a double dose of nebulized BUD, when either drug is added to bronchodilator therapy in children with mild asthma exacerbation.

Multinational, multicentre, randomized, active-controlled, parallel-group study

N=205; 12 weeks

Age= 18-65 years

Moderate persistent asthma, randomized to either

Respir Med. 2003 Feb;97 Suppl B:S35-40

Respir Med. 2003 Feb;97 Suppl B:S35-40

Chart1

5.25.8

5.25.7

baseline

final

mean PEF improvement

Sheet1

sputum eosinophil countblood eosinophil count

visit 1FP38%10%

visit 2FP3%7.30%

visit 1PDN52%7%

visit 2PDN11%2%

Sheet1

sputum eosinophil count

blood eosinophil count

Biological Markers

Sheet2

FPBDP

baseline5.25.2

final5.85.7

Sheet2

baseline

final

mean PEF improvement

Sheet3

ResultsThe two treatments were equally well tolerated.

Fluticasone propionate 2,000 mcg / day, is equally effective, with an acceptable safety and tolerability profile, when used in adult patients with moderate persistent asthma.

Respir Med. 2003 Feb;97 Suppl B:S35-40

Randomized, double-blind study,

Nebulized FP 2 mg BID (4 mg) vs. 0.5 mg BID (1 mg) with placebo

N= 301

Adult patients with oral steroid-dependent asthma.

Primary efficacy = reduction in daily oral steroid dose.

Secondary efficacy parameters Daily diary card peak expiratory flow (PEF), Day and night-time symptoms Clinic lung function measurements

Safety was assessed by adverse event monitoring and serum cortisol levels.

Respir Med. 1999 Oct;93(10):689-99

After 12 weeks of treatment the adjusted mean reduction in oral prednisolone was significantly greater in the FP 4 mg group compared other groups.Respir Med. 1999 Oct;93(10):689-99

A higher percentage of patients discontinued the use of oral steroids with FP 4 mg compared with other groups.Respir Med. 1999 Oct;93(10):689-99

PEFR improvement over 12 weeksRespir Med. 1999 Oct;93(10):689-99

Chart1

272297

293307

273300

baseline

12 weeks

Sheet1

baseline12 weeksPlacebo

FP 4 mg2722972

FP 1mg2933072

placebo2733003

Category 44.52.85

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FEV1 improvement over 12 weeksRespir Med. 1999 Oct;93(10):689-99

Chart1

1.571.71

1.631.71

1.491.62

baseline

12 weeks

Sheet1

baseline12 weeksSeries 3

FP 4 mg1.571.712

FP 1 mg1.631.712

placebo1.491.623

Category 44.52.85

To resize chart data range, drag lower right corner of range.

Other resultsFP 4 mg resulted in a significantly higher percentage of days when the patients were free from daytime (P = 0.036) and night-time (P = 0.021) wheeze, compared with placebo.

Significantly fewer patients withdrew from the FP 4 mg group compared with the other two groups.

All three treatments were well tolerated and the incidence of adverse events was similar between the groups.

FP Nebuliser suspension at a daily dose of between 1 and 4 mg are a safe and effective means of reducing the oral steroid requirement of patients with chronic oral steroid dependent asthma

Respir Med. 1999 Oct;93(10):689-99

The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study in COPD

26% reduction in the yearly rate of exacerbations in patients treated with FP compared to placebo.

Data support recommendations in the GOLD treatment guidelines that ICS should be considered in patients with moderate-to-severe COPD who experience recurrent exacerbations.

SummaryFluticasone propionate 2 mg / day is effective, with an acceptable safety and tolerability profile, when used in adult patients with moderate persistent asthma.

Nebulized fluticasone propionate is at least as effective as oral prednisolone in the treatment of acute exacerbation of asthma.

Nebulized fluticasone propionate is more effective than intravenous hydrocortisone and is associated with an early improvement.

SummaryA short course of nebulized fluticasone propionate has the same effects as a double dose of nebulized BUD.

Nebulized fluticasone propionate at a daily dose of between 1 and 4 mg are a safe and effective means of reducing the oral steroid requirement of patients with chronic oral steroid dependent asthma.

HIGHLIGHTSFP is first and the only nebulized corticosteroid approved for acute exacerbations of asthma in children 4 to 16 years.

Associated with faster clinical improvement.

Option for treatment of mild acute asthma attacks not requiring hospital admission.

Option for oral & IV steroids, in treatment of mild-moderate acute asthma.

Reduces dependence on oral steroids when used as maintenance therapy.

INDICATIONSFlohale respulesFor prophylactic management of severe chronic asthma in patients requiring high dose inhaled or oral corticosteroid therapy.

On introduction of fluticasone propionate many patients currently treated with oral corticosteroids may be able to reduce significantly, or eliminate, their oral dose.

DOSAGE AND ADMINISTRATIONAdults and adolescents over 16 years: 500-2,000 micrograms twice daily.

Volume of FLOHALE respules for nebulisationDosage in mg0.5 mg / 2 ml2 mg / 2 ml0.25 mg1 ml*-0.5 mg2 ml-0.75 mg3 ml-1 mg-1 ml1.5 mg-1.5 ml2 mg-2 ml3 mg-3 ml4 mg-2 respules* To be mixed with 0.9 % saline to make up a volume of at least 2 ml

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